This project involves the synthesis of new analogs of methotrexate (MTX), a widely used antineoplastic agent. On the basis of prior metabolic studies, these analogs (7-substituted derivatives) are predicted not only to be just as active, but also to be less toxic than MTX at a high dose or low dose regimen. Preliminary screening tests for the cytostatic activity of the MTX analogs using human leukemia cell lines K562 and CCRF/CEM will also be carried out. The metabolic study, effects on life span, presence or absence of organ impairments, and enzyme inhibitory activities will be investigated. The research will be carried out primarily by the principal investigator and two year college students who have demonstrated a potential or capability for biomedically related professions. Extensive collaborative arrangements have been established involving the Departments of Chemistry and Biochemistry, California State University, at Los Angeles and Dominguez Hills; Schools of Medicine and Pharmacy at the University of Southern California. These collaborations include sharing of equipment and interactions between our students and scientists as well as students in these institutions. This collaborations will also provide a greater exposure of our students to a variety of scientific research as well as hands-on experiences in other laboratories.